Compositions having high diuretic
tion and a high ratio of elimination
 of sodium with respect to potassium



The present invention relates to a new chemical compound of thechlorothiadiazide series having, in relation to the other members of theseries, remarkable properties which render it particularly valuable.This new compound is the potassium salt of 3-trichloromethyl-6-chloro 7sulphonamido-3,4-dihydro-benzo-1,2,4-thiadiazinel,l-dioxide, of theformula S03 Howls-pf iinc'ola The advantages of certain diureticsulphonamides, more particularly the compound hydrochlorothiazide, whichis 6 chloro7-sulphonamido-3,4-dihydro-benzo-1,2,4thiadiazine-l,1-dioxide arealready known.

The compound according-to the invention difi'ers advantageously fromhydrochlorothiazide and its derivatives which .are monoanddi-chlorornethylated in the 3-position firstly in the degree of itsdiuretic action, secondly in the sodium/ potassium elimination ratiowhich can be obtained by its use and, thirdly, in its field of activitywhich is distinctly different from that of hydrochlorothiazide and itsaforesaid derivatives.

The free acid form of the compound according to the invention may beprepared by condensing with cyclization the appropriate aromaticortho-aminosulphonamide with the appropriate aldehyde according to thefollowing reaction:

An example of this method of preparation is given hereunder.

EXAMPLE 10 grams (0.035 mol.) of 4-amino-6-chloro-benzene-1,3-disulphonamide were heated in a closed vessel at 100 C. for 20 hourswith 7.5 grams (0.045 mol.) of chloral hydrate in the presence of 1.5cc. of catalysing ammonia (solution having a density 0.925) and 40 cc.of water.

After cooling and filtration, the reaction mixture was dissolved inboiling 5% aqueous soda solution to form the mono-sodium salt of thedesired compound and the solution was cooled and filtered to separatethe unreacted reagents. The filtrate was acidified and thetrichloromethyl hydrochlorothiazide compound crystallised. The productwas drained, washed with water and dried, the yield obtained being 80%.

An example of a suitable method of forming the potassium salt is givenbelow:

PorAssrurt l 3 TRECHLOROMET'HYL 6 CHLORO 7 SUL- PHONAMIDO 3.4 DnrvnnoBmszo 1,2,4 Tammazmn 1,1 DlOXlDE (FS 207) i 3 ttichloromethyl 6 chloro 7sulphonamidoa 3,4 dihydro benzo 1,2,4 thiadiazine 1,1-

diortide grarns Potassium in pellet form do 20 Denatured absolutealcohol ml.... 300

The potassium was dissolved in the hot alcohol to give a yellow solutionand the sulphonamide was added thereto after cooling: The mixturecoagulated and the temperature increased to 30 C.; the paste then becamefluid and the salt formed became alkaline. The mixture was agitated andfiltered after one hour. The product obtained was washed with 50 cc. ofabsolute alcohol and dried at 35 C. until the weight was constant.

Obtained: 116 grams, that is a yield of 92.5 percent. The product iscompletely soluble in Water.

The characteristics of this potassium salt constituting the compoundaccording to the invention are as followsr it has a very smallsolubility in the aqueous acid solutions and is practically insoluble inthe organic solvents.

The characteristics of the potassium salt which constitute the compoundaccording to the invention are the following.

White crystalline powder, inodorous, slightly bitter to Ultra-violetspectrum: Maximum at 225 mu with an optic density not below 0.900(theory 0.945)

Minimum at 24?. m with an optic density near 0.080

Maximum at 267 run with an optic density not lower than 0.400 (theory0.430 with a slit width between 0.30 andv Minimum not very clear near250-295 my. with an optic density next to 0.060

Maximum not very clear near305-3l0 my with an optic density next to0.070

A null absorption above 350 my.

This potassium salt, contrary to the free acid form, is soluble in waterand may be administered either in the form of tablets, or in the .formof a solution which can be injected in doses containing from 25 to 200mg. of active principle.

In comparison with other known diuretic agents, the product according tothe present invention is distinguished by a whole series of advantages,some of which are entirely unexpected.

More particularly, active doses of the product according to theinvention are lower than the average doses of these diureticsulphonamides which are closest in their structure, while attaining amaximum level of action which is higher for this smaller dose and whilepreserving its efiectivencss for greater length of time. One of the mostimportant properties of the product according to the invention inrelation to those products which are closest in their structure, andmore particularly in rela-' tion to hydrochlorothiazide and mono ordichloromethyl hydrochlorothiazide, is the fact that the vproduct according to the-invention has a ratio of elimination of sodium in proportionto potassium which is substantially more Patented Aug. 31,

3,203,861 3 favourable WithOUt any symptom of acutfi Or Chronic TAELE1UNSALIFIED BULPHONAWDE ADMINISTERED toxicity. IN SUSPENSION Givenhereunder by way of illustration of the general pharmacologicalproperties are comparative measurem Elimination ments of diureticactivity, in the first place between the sulphcnimide, mums, Na/Kproduct according to the invention and hydrochlorodose ms-l s. p rcentNa [E of thiaiide, in the second place between the product acf gg i hcording to the invention, that is to say the potassium salt oftrichloromethyl hydrochlorothiazide and the same 0 2&9 97 use L2compound but in the unsalified acid form, that is to say g 23.3 &1 {$23.? trichloromethyl hydrochlorothiazide itself, and in the third 5 L6.place between the product according to the invention and 8- ;g 1 2% t gdiohloromethyl hydrochlorothiazidc.

(1) Comparative study between hyjzirochlorothiazzde and Contrary to theunsalified sulphonamide the Potassium the product according tot eInvention salt enables a clear solution to be obtained which has a.

The tests, which were applied to a total of more than shghtiy l h 2,000animals, were carried out On groups of 100 rats, Solution adm1mtered bythe buccal method in the first placfi with increasing doses (ofhydrochlorm the test rat (same technique as before) enables a diuresisthiazide and then with the same doses of hydrochlorothiazide associatedwith constant doses of the product according to the invention.

The results have been expressed in percentage of diuresis and ofelimination of sodium and potassium respective in relation to the weightof the animal in kilograms. The first part of these results establishesthat the maximum diuresis obtainable with hydrochlorothiazide alone doesnot exceed about 75 even by doubling the dose beyond 5 mg./kg., whereasin the same animals the addition of a small quantity of the productaccording to the invention, designated by the code PS 207, whichquantity does not itself enable a diuresis greater than 5060% to beobtained in control animals, results in a considerable increase in thediuresis of the animals. It will be noted that this increase is found inthe diureses of water and sodium, whereas the potassium diuresis ispractically speaking not increased. These results constitute proof thatthe ways in which the two types of sulphonamides act are diiferent andthat the addition of the product according to the invention to atreatment with hydrochlorothiazide enables the ceiling which limited theaction of hydrochlorothiazide to be raised very substantially.

MgJkg. Elimination Elimination Dlurosis of sodium of potassium (percent)rug/kg of lug/kg of Hydrochloro- PS 207 body weight body weight thiazide2. 5 O 60. 7 8. 34 1. 01 5 0 78. l. 3. 9 L 50 10 0 77. 1 4. 1 1. 40 2.5 1. 79. 3 4. 2 1. 5 l. 25 91. 2 4. 7 1. 30 10 1. 25 84. 6 4. 3 I.Control 0 1. 25 67. 0 3. 1 1. 00

(2) Comparative action of the product according lo the invention(potassium salt) and the unsalified product (referred to as basesulphonamide) of water of 67% of the starting overload with 5 mg./kg. ofactive substance, 75% with 10 mg. and 101% for a dose of 20 mg. to beobtained.

TABLE 2.SALIFIED SULPHONAMIDE ACCORDING TO The threshold dose ofactivity may be fixed at around 0.5 mg./kg. with the technique employed,the threshold dose of hydrochlorothiazide, under the same conditions,being greater than 5 mgJkg. It is to be observed that the threshold ofactivity of sodium diuresis is much lower since, in anaesthetised dogs,a saline diuresis is obtained for a threshold dose of 0.1 mg./kg. ofproduct, while a water diuresis threshold dose of the order of 5 mg./kg. is obtained.

The ditference between the action of the potassium salt and of the basesulphonamide is particularly clear from the evolution of thesodium/potassium elimination ratio.

TABLE 3.-RATIO OF ELIMINATION OF SODIUM TO PO TASSIUM OBTAINED IN RATSWITH THE UNSALIFIED BASE SULPHONAMIDE IN A UEOUS SUSPENSION (TESTSCARRIED OUT ON AN LS) 4 Dose of unsallfied case sulphonamide, Na/K, inmlllimoles rug/kg.

With the strong doses a slight increase in the ratio may be noted; thisconfirms the tow diuretic activity round according to the volume 0!urine and the elimination of salts.

Whereas the most favourable ratio (increase in sodium for a slightincrease in potassium) found with the base sulphonamide is less than 2for a dose of 40 mgJkg. of product, the potassium salt according to theinvention enables ratios as high as 5 to be obtained for a dose of 2.5nag/kg.

TABLE 4.Na/K' ELIMINATION RATIO OBTAINED WITH THE PRODUCT ACCORDING TOTHE INVENTION IN RATS (TESTS CARRIED OUT ON 264 ANIMALS) Doses of Testspotassium salt, mgJkg. 1 2 3 4 6 6 7 8 It is to he noted that this ratiois more favourable than those obtained, whatever the dose of substance,both with acetazolamide and with chlorothiazide or hydrochlorothiazide,which are relatively closely related products and the activities andproperties of which may be taken as terms of comparison as regards theproduct according to the invention.

TABLE 5.-No/K RATIO OBTAINED WITH VARIOUS DIU- REIIC SSBTLPHONAMIDES(TESTS CARRIED OUT ON 272 ANIMAL Tests Dose of diuretic, rug/kg.

Acetozolamide:

TABLE 6.Na/K RATIO OBTAINED WITH ANAESTHE- TISED DOGS KEPT UNDERHYDROSALINE OVERLOAD AND RECEIVING THE DIURETIC INTRAVENOUSLY [Productaccording to the invention: K salt (PS 207 Control values:5.5-4.2-5.56.'5]

Values Doses mg./kg.: obtained 0.1 6.4 1 7.4 10 8.4 50 11.4

[Hydrochiorothiazide-Control values: 3-4.7]

Average of 8 experiments with 15 mgJkg. hydrochlorothiazine It is foundin anaesthetised dogs under hydrosaline overload that the Na/K ratio mayattain values higher than 10, after administration of the productaccording to the invention, whereas under the same conditions it is notpossible to obtain ratios higher than 6 with hydrochlorothiazide.

The respective activities of the dichloromethylated derivative and theh'ichloromethylated derivative (unsalified hase sulphonamide), comparedwith that of hydrochlorothiazide, have been found to be of the order of15 times and 0.5 time that of the reference product(hydrochlorothiazide).

it is thus entirely surprising to find that, on the other hand, thepotassium salt of the trichloromethylated deriyative (PS 207) has anactivity slightly greater than that of the dichloromethyiated derivativeand of the order of 20 times that of hydrochlorothiazide. These resultswere obtained with dogs and rats under experimental conditions similarto those described above. Moreover, another distinct and surprisingadvantage of PS 207 with respect to the dichioromethylated derivativehas been found, namely that the potassium diuresis of thedichloromethylated derivative is greater than that of hynegligibleelimination of potassium, whereas the unsalified base sulphonamide isonly slightly diuretic, to the extent of about halt as much ashydrochlorothiazide itself.

in forty cases involving congestive cardiac insuificiency withperipheral edema, twenty-three patients had arterial cardiopathy withpredominating insufficiency of the left ventricle and a senile heart,other patients had an insufliciency or" the right ventricle resultingfrom a chronic pulmonary heart, whilst some others had decompensatedvalvular cardiopathy. The doses used were very small, of the order of0.10 gram per day, and were administered in two portions. It will benoted that 0.055 gram of potassium salt is equivalent to 0.050 gram ofthe base sulphonamide.

in all the cases observed, no case of digestive intolerance were founddue to direct action of the product, nor any clinical hypochloremia,hyponatremia or hypokalemia disorders. in addition, no notablestatistical difference was observed in the pH value of the blood.

I claim:

it. A pharmaceutical composition for the treatment of edematonsconditions and ior enhancing the rate of excretion of sodium ions whilemaintaining the rate of ex-- cretion of potassium ions, said compositioncomprising 0.025 to 0.200 gram or the potassium salt ofB-trichloromethyl-fi-chloro 7 sulphonamido 3,4 dihydrobenzo-1,2,4-thiadiazine-Ll-dioxide of the formula S09 Hal-10:3

Cl (JH-C 01,

in admixture with a pharmaceutical carrier.

2. A process for enhancing the excretion of sodium ions and maintainingthe rate of excretion of potassium ions in a patient sufier'mg fromedema, said process comprising administering to the patient apharmaceutical 7 8 composition comprising 0.025 to 0.200 gram of the110- OTHER REFERENCES tassium salt of3-trichloromthyl-(S-chloroJ-sulphonamide-3,4-dihydrobenzo-l,2,4-thiadiazine-1,1-dioxide and 2iig5 f;;?ff;volume pages Pharmacwucal camel" Experientia, volume 16, No. 3, 1960,page 113.-

5 Federation Proceedings, vol. 18, No. 1, part 1, abstract ReferencesCited by the Examiner No. 1563, page 396 (March 1956).

UNITED STATES PATENTS FRANK CACCIAPAGLIA,JR. P ma Exam'ne 3,040,042 6/62Yale et a1 260-243 r 3 0 1 301 I 3 3 ])6 Stevens et 1 1 7 50 10 IRVINGMARCUS, NICHOLAS S. RIZZO, Examiners.

1. A PHARMACEUTICAL COMPOSITION FOR HTE TREATMENT OF EDEMATOUSCONDITIONS AND FOR ENHANCING TEH RATE OF EXCRETION OF SODIUM IONS WHILEMAINTAINING THE RATE OF EXCRETION OF POTASSIUM IONS, SAID COMPOSITIONCOMPRISING 0.025 TO 0.200 GRAM OF THE POTASSIUM SALT OF3-TRICHLOROMETHYL-6-CHLORO - 7 - SULPHONAMIDO - 3,4 -DIHYDROBENZO1,2,4-THIADIAZINE-1,1-DIOXIDE OF THE FORMULA